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Some Light in the Dark

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Two mutations that collectively occur in 71 percent of malignant melanoma tumors have been discovered in regions of the DNA of cancer cells where cancer-related mutations haven’t previously been found.

Reporting in the February 22 issue of Science, HMS researchers from Dana–Farber Cancer Institute and the Broad Institute of MIT and Harvard say the mutations may be the most common found to date in melanoma cells.

These cancer-associated mutations are the first to be discovered in the 99 percent of the cancer genome that does not contain genetic instructions for making proteins, a functional absence that has, up to now, led scientists to consider this vast expanse of DNA as “junk.” A large number of oncogenic mutations in cancer have been identified in the past several decades, but all have been found within the actual genetic blueprints for proteins.

“This new finding represents an initial foray into the ‘dark matter’ of the cancer genome,” says senior author Levi Garraway ’00, an HMS associate professor of medicine at Dana–Farber and an associate member of the Broad.

The mutations affect a promoter region—a stretch of DNA code that controls the rate at which a gene is transcribed—adjacent to the TERT gene. TERT contains the recipe for making telomerase reverse transcriptase, an enzyme that can make cells virtually immortal, and is often found overexpressed in cancer cells.

The scientists say the same mutations are present in cell lines from some other malignancies, and that preliminary evidence shows they might be unusually common in bladder and liver cancers. The researchers also note that the discovery highlights the value of whole-genome searches of tumor DNA.